CN103073552B - A kind of unformed Citric Acid holder method is for the preparation method of Buddhist nun - Google Patents
A kind of unformed Citric Acid holder method is for the preparation method of Buddhist nun Download PDFInfo
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- CN103073552B CN103073552B CN201310046162.4A CN201310046162A CN103073552B CN 103073552 B CN103073552 B CN 103073552B CN 201310046162 A CN201310046162 A CN 201310046162A CN 103073552 B CN103073552 B CN 103073552B
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- Prior art keywords
- citric acid
- buddhist nun
- unformed
- acid holder
- holder method
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 238000000034 method Methods 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 238000007605 air drying Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 4
- 238000001556 precipitation Methods 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- -1 7H-pyrrolo-[2,3-d] pyrimidine-4-yl Chemical group 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 102000015617 Janus Kinases Human genes 0.000 description 2
- 108010024121 Janus Kinases Proteins 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012716 precipitator Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940039916 xeljanz Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the preparation method of a kind of unformed Citric Acid holder method for Buddhist nun, described preparation method is easy, is easy to obtain highly purified unformed Citric Acid holder method for Buddhist nun, is applicable to industrial application.Preparation method of the present invention, comprise the following steps: at the temperature of 30-50 DEG C of scope, solution is formed for Buddhist nun by organic solvent dissolution Citric Acid holder method, this solution is added in the water of 15-25 DEG C and form precipitation, this throw out is placed on 4-24 hour in the environment of 15-25 DEG C, then unformed Citric Acid holder method is reclaimed for Buddhist nun.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the preparation method of a kind of unformed Citric Acid holder method for Buddhist nun.
Background technology
Citric Acid holder method is 3-{ (3R for the chemical formula of Buddhist nun, 4R)-4-methyl-3-[methyl (7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl-3-oxypropionitrile citrate, its structural formula, such as formula shown in I, is a kind of Janus kinases (JAKs) inhibitor that Pfizer (Pfizer) researches and develops.On November 6th, 2012, FDA (Food and Drug Adminstration) (FDA) ratifies Citric Acid holder method for Buddhist nun (Xeljanz) listing, for methotrexate for treatment underaction or the moderate that do not tolerate to the treatment of severe Active rheumatoid arthritis (RA) adult patient.
Formula I
Patent WO2012135338 discloses and a kind ofly prepares unformed Citric Acid holder method for the method for Buddhist nun, holder method is mainly first obtained holder method for Buddhist nun's acetate for Buddhist nun's free alkali and acetic acid salify by it, then by holder method in the water-soluble or methyl alcohol of Buddhist nun's acetate, add Citric Acid to make it to be converted into holder method for Buddhist nun's citrate, obtain unformed Citric Acid holder method for Buddhist nun finally by methods such as lyophilize, vacuum-drying, spraying dry.This preparation method operation is more loaded down with trivial details, and in the product obtained, impurity is more, comprises holder method for impurity such as Buddhist nun's acetate, reduces purity and the quality of product.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of unformed Citric Acid holder method for Buddhist nun (structural formula I).
Preparation method's operating process of the present invention is simple, lower to equipment requirements, and effectively raises the purity of product and stability and solubleness.
Unformed Citric Acid holder method of the present invention, for the preparation method of Buddhist nun, comprises the following steps:
At the temperature of 30-50 DEG C of scope, form solution by organic solvent dissolution Citric Acid holder method for Buddhist nun, this solution is added in the water of 15-25 DEG C and form precipitation, this throw out is placed on 4-24 hour in the environment of 15-25 DEG C, then unformed Citric Acid holder method is reclaimed for Buddhist nun.
Unformed Citric Acid holder method of the present invention, for Buddhist nun, can also adopt following preparation method:
At the temperature of 30-50 DEG C of scope, solution is formed for Buddhist nun by organic solvent dissolution Citric Acid holder method, this solution is added in the anti-solvent of 25-30 DEG C of temperature range and form precipitation, this throw out is placed on 4-24 hour in the environment of 25-30 DEG C, then unformed Citric Acid holder method is reclaimed for Buddhist nun.
Unformed Citric Acid holder method of the present invention, for Buddhist nun, can also adopt following preparation method:
At the temperature of 30-50 DEG C of scope, form solution by organic solvent dissolution Citric Acid holder method for Buddhist nun, by this solution spraying dry at 30-35 DEG C, collect solid.
Wherein, described organic solvent includes but not limited to, polar aprotic solvent or aprotic solvent and their mixture.Comprise alcohols, preferably (C
1-C
6)-alkyl alcohol is as methyl alcohol and ethanol; Ketone, preferably (C
1-C
6)-alkyl ketone is as acetone; With acid amides as dimethyl formamide etc.Particularly preferred solvent comprises ethanol and acetone.
Wherein, described anti-solvent includes but not limited to ester class, ethyl acetate; Ethers, preferred diisopropyl ether; With alkane as normal hexane, hexanaphthene etc., particularly preferred solvent comprises ethyl acetate and hexanaphthene.
Wherein, described Citric Acid holder method belongs to currently available products for Buddhist nun, commercially can buy, also can prepare according to prior art.
The invention provides the unformed Citric Acid holder method of preparation for Buddhist nun.With the Citric Acid holder method of other known type for the unformed Citric Acid holder method of Buddhist nun and previous known type for compared with Buddhist nun, unformed Citric Acid holder method as herein described has better solubleness and stability for Buddhist nun.In addition, preparation method of the present invention is simple, and cost is low, is more suitable for scale operation.
Beneficial effect of the present invention is further illustrated by following experiment.
Table 1 unformed Citric Acid holder method of the present invention replaces the related substance situation under each influence factor of Buddhist nun for unformed Citric Acid holder method prepared by Buddhist nun and patent (WO2012135338) method
Test-results shows, and unformed Citric Acid holder method of the present invention all shows satisfactory stability for Buddhist nun under high temperature, super-humid conditions, is all better than unformed Citric Acid holder method prepared by patent (WO2012135338) method for Buddhist nun under each influence factor.
Accompanying drawing explanation
Accompanying drawing 1: embodiment 1 unformed Citric Acid holder method is for the X-diffracting spectrum of Buddhist nun.
Accompanying drawing 2: embodiment 2 unformed Citric Acid holder method is for the X-diffracting spectrum of Buddhist nun.
Accompanying drawing 3: embodiment 3 unformed Citric Acid holder method is for the X-diffracting spectrum of Buddhist nun.
Embodiment
By following specific embodiment, the present invention is further illustrated, but not as restriction.
Embodiment 1: the precipitator method prepare unformed Citric Acid holder method for Buddhist nun's (ethanol-water system)
5g Citric Acid holder method is added in reaction flask for Buddhist nun, add 20mL ethanol, be heated to 30-35 DEG C, make solid entirely molten, this solution is joined in the water of 20mL15-25 DEG C, at 15-25 DEG C, stir gained suspension about 16 hours, filter, gained solid ethanol/water (volume ratio 1:1) washs, 60 DEG C of forced air dryings are to constant weight, obtain unformed Citric Acid holder method for Buddhist nun 4.5g, yield is 95%, HPLC purity assay is 99.6%.
Embodiment 2: the precipitator method prepare unformed Citric Acid holder method for Buddhist nun's (methanol-ethyl acetate system)
50g Citric Acid holder method is added in reaction flask for Buddhist nun, add 100mL methyl alcohol, be heated to 30-35 DEG C, make solid entirely molten, this solution is joined in the ethyl acetate of 50mL25-30 DEG C, at 25-30 DEG C, stir gained suspension about 20 hours, filter, gained solids with methanol/ethyl acetate (volume ratio 2:1) is washed, 60 DEG C of forced air dryings are to constant weight, obtain unformed Citric Acid holder method for Buddhist nun 45.8g, yield is 91.6%, HPLC purity assay is 99.7%.
Embodiment 3: spray-drying process prepares unformed Citric Acid holder method for Buddhist nun
At about 30-35 DEG C, 50g Citric Acid holder method is dissolved in 100mL methyl alcohol, by this solution to carry out spraying dry in the flow velocity 30 DEG C to 35 DEG C of about 2.5 ml/min, 600 newton l/h nitrogen gas stream for Buddhist nun.Recover materials from susceptor, the 60 DEG C of forced air dryings of gained solid are to constant weight, and obtain unformed Citric Acid holder method for Buddhist nun 46.8g, yield is 93.6%, HPLC purity assay is 99.5%.
Claims (3)
1. unformed Citric Acid holder method is for a Buddhist nun's preparation method, comprises the following steps:
5g Citric Acid holder method is added in reaction flask for Buddhist nun, add 20mL ethanol, be heated to 30-35 DEG C, make solid entirely molten, this solution is joined in the water of 20mL 15-25 DEG C, at 15-25 DEG C, stir gained suspension 16 hours, filter, the gained solid ethanol/water of volume ratio 1:1 washs, and 60 DEG C of forced air dryings, to constant weight, obtain unformed Citric Acid holder method for Buddhist nun 4.5g.
2. unformed Citric Acid holder method is for a Buddhist nun's preparation method, comprises the following steps:
50g Citric Acid holder method is added in reaction flask for Buddhist nun, add 100mL methyl alcohol, be heated to 30-35 DEG C, make solid entirely molten, this solution is joined in the ethyl acetate of 50mL 25-30 DEG C, at 25-30 DEG C, stir gained suspension 20 hours, filter, the gained solid methanol/ethyl acetate of volume ratio 2:1 is washed, and 60 DEG C of forced air dryings, to constant weight, obtain unformed Citric Acid holder method for Buddhist nun 45.8g.
3. unformed Citric Acid holder method is for a Buddhist nun's preparation method, comprises the following steps:
At 30-35 DEG C, 50g Citric Acid holder method is dissolved in 100mL methyl alcohol for Buddhist nun, by this solution to carry out spraying dry in flow velocity 30 DEG C to 35 DEG C, 600 ls/h nitrogen gas stream of 2.5 ml/min, recover materials from susceptor, the 60 DEG C of forced air dryings of gained solid, to constant weight, obtain unformed Citric Acid holder method for Buddhist nun 46.8g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310046162.4A CN103073552B (en) | 2013-02-05 | 2013-02-05 | A kind of unformed Citric Acid holder method is for the preparation method of Buddhist nun |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310046162.4A CN103073552B (en) | 2013-02-05 | 2013-02-05 | A kind of unformed Citric Acid holder method is for the preparation method of Buddhist nun |
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| CN103073552A CN103073552A (en) | 2013-05-01 |
| CN103073552B true CN103073552B (en) | 2015-08-12 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104292231B (en) * | 2013-09-17 | 2016-11-30 | 广东东阳光药业有限公司 | A kind of citric acid expelling pathogens by strengthening vital QI is for the preparation method of Buddhist nun |
| WO2015051738A1 (en) * | 2013-10-08 | 2015-04-16 | Sunshine Lake Pharma Co., Ltd. | Tofacitinib citrate |
| CN104774206A (en) * | 2014-01-14 | 2015-07-15 | 江苏柯菲平医药股份有限公司 | New method for preparing tofacitinib citrate crystal-form A |
| CA2881262A1 (en) | 2014-02-06 | 2015-08-06 | Prabhudas Bodhuri | Solid forms of tofacitinib salts |
| CN104459004B (en) * | 2014-12-16 | 2016-03-09 | 南京艾德凯腾生物医药有限责任公司 | Content determination and related substance detection method of tofacitinib citrate |
| CN106831710A (en) * | 2015-12-07 | 2017-06-13 | 常州爱诺新睿医药技术有限公司 | A kind of solid dispersions of unformed HKI-272 or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| CN108794491B (en) * | 2018-08-16 | 2020-02-18 | 山东罗欣药业集团恒欣药业有限公司 | Refining method of tofacitinib citrate |
| CN109824676A (en) * | 2019-04-23 | 2019-05-31 | 天地恒一制药股份有限公司 | A kind of support method replaces preparation method and application of the cloth in relation to substance |
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| WO2012135338A1 (en) * | 2011-03-28 | 2012-10-04 | Ratiopharm Gmbh | Processes for preparing tofacitinib salts |
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2013
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Effective date of registration: 20160830 Address after: 100028 Beijing City, Chaoyang District Shuguang Sirirath A Phoenix Plaza No. 5 block 27 layer Patentee after: BEIJING PHARMACEUTICAL GROUP Co.,Ltd. Address before: 100124 Beijing city Chaoyang District Baiziwan West No. 402 Business Center No. 2 Fu Jinhai floor 21 Patentee before: CHINA RESOURES SAIKE PHARMACEUTICAL Co.,Ltd. |
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